PROJECT SUMMARY GeoVax, a clinical-stage biotechnology company focusing on vaccine development against infectious diseases and cancer, seeks to build on its successful vaccine candidate against Lassa virus (LASV) to implement a novel immunogen design for eliciting broadly cross-reactive neutralizing antibodies. LASV is a member of the Arenaviridae family and is endemic in West Africa where it infects 100,000-300,000 persons each year, with approximately 5,000 deaths. No vaccine is currently under clinical development for the prevention of LASV infection. GeoVax created a vaccine against LASV (GEO-LM01) using its proven Modified Vaccinia Ankara (MVA) Virus-Like Particle (VLP) platform. GEO-LM01 incorporates into the MVA genome LASV sequences encoding both a glycoprotein (GPC) and a matrix protein (Z). Upon infection of human cells, the MVA-driven expression of these proteins results in the budding from the surface of the infected cells of VLPs that bear natively-folded GPC on their surface. Pre-clinical testing of GEO-LM01 in a lethal mouse model demonstrated 100% protection after a single dose with strong T cell responses yet meagre antibody responses, in line with other vaccine candidates tested in animals. Capitalizing on recent breakthroughs in the structural characterization of LASV GPC, we propose in this Fast-Track Phase I/II application to develop and test novel GPC immunogen designs in the context of the MVA-VLP system. Phase I will consist of sequence design, MVA-VLP construction, in vitro testing, and efficacy and immunogenicity studies in an established lethal mouse model. In Phase II, GEO-LM01 and the selected new vaccine candidate will be produced at high titers and tested against all four major lineages of LASV in the established Hartley guinea pig challenge model. Both vaccines will then be tested for efficacy in non-human primates and will be concomitantly evaluated extensively for the magnitude and characteristics of the cellular and humoral immune responses. The final down-selected vaccine candidate will be tested for genetic stability and sterility in preparation for cGMP manufacturing and a Phase 1 clinical study.